Novel pyrazine compounds as transforming growth factor (TGF) compounds

ABSTRACT

Novel pyrazine compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of transforming growth factor (“TGF”)-β signaling pathway. They are useful in the treatment of various TGF-related disease states including, for example, cancer and fibrotic diseases.

RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C.119(e) to U.S. Provisional Application No. 60/453,784, filed Mar. 11,2003, which is incorporated herein in its entirety by reference.

BACKGROUND OF THE INVENTION

[0002] The present invention relates to novel pyrazine compounds,including derivatives thereof, to intermediates for their preparation,to pharmaceutical compositions containing them and to their medicinaluse. The compounds of the present invention are potent inhibitors of thetransforming growth factor (“TGF”)-β signaling pathway. They are usefulin the treatment of TGF-β related disease states including, for example,cancer and fibrotic diseases.

SUMMARY OF THE INVENTION

[0003] The invention provides a compound of formula (I):

[0004] or a pharmaceutically acceptable salt, prodrug, hydrate orsolvate thereof where:

[0005] R¹ is H;

[0006] R² is a substituted or unsubstituted (C₁-C₈)alkyl,(C₃-C₉)cycloalkyl, (C₃-C₉)aryl, (C₃-C₉)heteroaryl, amide, amino,(C₁-C₈)alcohol, (C₃-C₉)heterocycloalkyl, (C₃-C₉)aryl(C₁-C₈)alkyl,amino(C₁-C₈)alkyl, amido(C₁-C₈)alkyl; or R¹ and R² taken together withthe nitrogen to which they are attached form a substituted orunsubstituted heterocycloalkyl or heteroaryl;

[0007] R³ is independently selected from the group consisting of H,(C₁-C₈)alkyl, halo, (C₁-C₈)alkoxy, sulfonyl, cyano, and keto;preferably, H, bromo, chloro, cyano, methoxy, (C₁-C₈)alkyl-SO₂—, and(C₁-C₈)alkylC(═O)—;

[0008] n is an integer from 0-5; preferably, 0-4; more preferably, 0-1,

[0009] with the proviso that the compound is not3-amino-6-phenyl-pyrazine-2-carboxylic acid butylamide or3-amino-6-phenyl-pyrazine-2-carboxylic acid (2-hydroxy-ethyl)-amide.

[0010] The invention also provides a compound of formula (II):

[0011] or pharmaceutically acceptable salt, prodrug, hydrate or solvatethereof where:

[0012] R¹ is H;

[0013] R² is a substituted or unsubstituted (C₁-C₈)alcohol,(C₃-C₉)cycloalkyl, (C₃-C₉)heterocycloalkyl, (C₃-C₉)heteroaryl,amino(C₁-C₈)alkyl, (C₃-C₉)aryl(C₁-C₈)alkyl, or amido(C₁-C₈)alkyl; or R¹and R² taken together with the nitrogen to which they are attached forma substituted or unsubstituted heterocycloalkyl or heteroaryl group;

[0014] Het is a substituted or unsubstituted heterocyclyl or heteroarylgroup containing at least one heteroatom selected from N, O and S;preferably, a substituted or unsubstituted (C₅-C₁₀)heterocyclyl orheteroaryl group containing at least one heteroatom selected from N, Oand S; more preferably, a substituted or unsubstituted furanyl, thienyl,pyridyl, or benzofuranyl group.

[0015] The invention further provides a compound of formula (III):

[0016] or a pharmaceutically acceptable salt, prodrug, hydrate orsolvate thereof where:

[0017] R¹ is H;

[0018] R² is a substituted or unsubstituted (C₁-C₈)alcohol; preferably,a substituted or unsubstituted (C₁-C₅)alcohol; more preferably, asubstituted or unsubstituted (C₃-C₅)alcohol;

[0019] Ar is a substituted or unsubstituted (C₃-C₉)aryl group;preferably a substituted or unsubstituted naphthyl group,

[0020] with the proviso that the compound is not3-amino-6-phenyl-pyrazine-2-carboxylic acid butylamide or3-amino-6-phenyl-pyrazine-2-carboxylic acid (2-hydroxy-ethyl)-amide.

[0021] Suitable substituents for a compound of formula (I), (II) or(III), each as set forth above, are as defined below and also includethose set forth in the Examples below. Preferably, the substituent isone as set forth in the Examples below. Furthermore, any twosubstituents on adjacent carbons can be taken together with the atoms towhich they are attached to form a carbocyclic, non-aromatic or aromaticmoiety which optionally contains at least one heteroatom selected fromthe group consisting of N, O and S. Still further, a substituent can befurther substituted (e.g., benzyl-piperazine). A compound of theinvention may contain more than one substituent.

[0022] The invention still further provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically acceptablecarrier, each as described herein.

[0023] The invention further provides a method of preparation of acompound of the invention.

[0024] The invention also provides a method of preventing or treating aTGF-related disease state in a mammal (animal or human) comprising thestep of administering a therapeutically effective amount of a compoundof the invention to the animal or human suffering from the TGF-relateddisease state, each as described herein. In a preferred embodiment, theTGF-related disease state is selected from the group consisting ofcancer, glomerulonephritis, diabetic nephropathy, hepatic fibrosis,pulmonary fibrosis, intimal hyperplasia and restenosis, scleroderma, anddermal scarring.

[0025] A compound of the invention can be used in the manufacture of amedicament for the prophylactic or therapeutic treatment of aTGF-related disease state in a mammal (animal or human).

Definitions

[0026] As used herein, the article “a” or “an” refers to both thesingular and plural form of the object to which it refers unlessindicated otherwise.

[0027] As used herein, the term “alkyl,” as well as the alkyl moietiesof other groups referred to herein (e.g., alkoxy) refers to a linear orbranched saturated hydrocarbon (e.g., methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl).

[0028] As used herein, the term “cycloalkyl” refers to a mono orbicyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl).

[0029] As used herein, the term “halogen” or “halo” refers to includesfluoro, chloro, bromo or iodo or fluoride, chloride, bromide or iodide.

[0030] As used herein, the term “halo-substituted alkyl” or “haloalkyl”refers to an alkyl radical, as set forth above, substituted with one ormore halogens, as set forth above, including, but not limited to,chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, and 2,2,2-trichloroethyl.

[0031] As used herein, the term “alkenyl” refers to a linear or branchedhydrocarbon chain radical containing at least two carbon atoms and atleast one double bond. Examples include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, and 2-butenyl.

[0032] As used herein, the term “alkynyl” refers to a linear or branchedhydrocarbon chain radical having at least one triple bond including, butnot limited to, ethynyl, propynyl, and butynyl.

[0033] As used herein, the term “carbonyl” refers to a >C═O moiety.Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refers to an alkyl carbamategroup. The carbonyl group is also equivalently defined herein as (C═O).

[0034] As used herein, the term “phenyl-[(alkyl)-N]—(C═O)—” refers to aN.N′-disubstituted amide group of the formula

[0035] As used herein, the term “aryl” refers to an aromatic radicalsuch as, for example, phenyl, naphthyl, tetrahydronaphthyl, and indanyl.

[0036] As used herein, the term “heteroaryl” refers to an aromatic groupcontaining at least one heteroatom selected from O, S and N. Forexample, heteroaryl groups include, but are not limited to, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl,pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g.,1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g.,1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, and indolyl.

[0037] As used herein, the term “heterocycle”, “heterocyclyl” or“heterocyclic” refers to a saturated, unsaturated or aromatic C₃-C₂₀mono-, bi- or polycyclic group containing at least one heteroatomselected from N, O, and S. Examples of heterocyclic groups include, butare not limited to, azetidinyl, tetrahydrofuranyl, imidazolidinyl,pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl,pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl,tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl,oxazinyl, oxcithiazinyl, indolinyl, isoindolinyl, quincuclidinyl,chromanyl, isochromanyl, benzocazinyl, and the like. Examples ofmonocyclic saturated or unsaturated ring systems aretetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl,isothiazolidine, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,1,3-pyrazolidin-1-yl, thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,and 1,2,5-oxathiazin-4-yl.

[0038] The term “oxo” refers to a double bonded oxygen moiety, i.e., ═O.

[0039] As used herein, the term “pharmaceutically acceptable acidaddition salt” refers to non-toxic acid addition salts, ie., saltsderived from pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate [ie.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

[0040] As used herein, the term “pharmaceutically acceptable baseaddition salt” refers to non-toxic base addition salts, i.e., saltsderived from such pharmacologically acceptable cations such as alkalimetal cations (e.g., potassium and sodium) and alkaline earth metalcations (e.g., calcium and magnesium), ammonium or water-soluble amineaddition salts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

[0041] As used herein, the term “suitable substituent”, “substituent” or“substituted” refers to a chemically and pharmaceutically acceptablefunctional group, i.e., a moiety that does not negate the inhibitoryand/or therapeutic activity of the inventive compounds. Such suitablesubstituents may be routinely selected by those skilled in the art.Illustrative examples of suitable substituents include, but are notlimited to, cycloalkyl, heterocyclyl, alcohol, benzyl, carbonyl, halo,haloalkyl, perfluoroalkyl, perfluoroalkoxy, alkyl, alkenyl, alkynyl,hydroxy, oxo, mercapto, alkylthio, alkoxy, aryl or heteroaryl, aryloxyor heteroaryloxy, aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy,HO—(C═O)—, ester, amido, ether, amino, alkyl- and dialkylamino, cyano,nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, alkylsulfonyl,arylsulfonyl and the like. Those skilled in the art will appreciate thatmany substituents can be substituted by additional substituents.

[0042] As used herein, the term “TGF-related disease state” refers toany disease state mediated by the production of TGF-β.

DETAILED DESCRIPTION OF THE INVENTION

[0043] A compound of the invention may be prepared according to theSchemes and Examples as described below. Unless otherwise indicated, allvariables in the reaction schemes and discussion that follow are each asdefined herein.

[0044] In reaction (i) of Scheme 1, compound A is reacted with a boronicacid of formula

[0045] in the presence of a catalyst, such as, for example, Pd(dppb)Cl₂,Pd(PPh₃)₄, or bis-(diphenylphosphino)ferrocene/palladium acetate, in anaprotic solvent, such as dimethylformamide, at a temperature betweenabout 30° C. to about 130° C., preferably, about 90° C., and for a timeperiod between about 2 hours to about 24 hours, preferably, about 12hours, to form compound B. In reaction (ii) of Scheme 1, compound B isthen subjected to hydrolysis conditions to form the corresponding acidof compound C. In reaction (iii) of Scheme 1, compound C is reacted withamine R²NH₂ to form the amide compound D.

[0046] In reaction (i) of Scheme 2, compound E is reacted with boronicacid of formula Het-B(OH)₂ in the presence of a catalyst, such as, forexample, Pd(dppb)Cl₂, Pd(PPh₃)₄, orbis-(diphenylphosphino)ferrocene/palladium acetate, in an aproticsolvent, such as dimethylformamide, at a temperature between about 30°C. to about 130° C., preferably, about 90° C., and for a time periodbetween about 2 hours to about 24 hours, preferably, about 12 hours, toform compound F. In reaction (ii) of Scheme 2, compound F is thensubjected to hydrolysis conditions to form the corresponding acid ofcompound G. In reaction (iii) of Scheme 2, compound G is reacted withamine R²NH₂ to form the amide compound H.

[0047] All pharmaceutically acceptable salts, prodrugs, hydrates andsolvates of a compound of formulae (I), (II), or (III) are encompassedby the present invention.

[0048] A compound of the invention which is basic in nature is capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals and humans, it is often desirable inpractice to initially isolate a compound of the invention from thereaction mixture as a pharmaceutically unacceptable salt and then simplyconvert the latter back to the free base compound by treatment with analkaline reagent, and subsequently convert the free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent such as, for example, methanol or ethanol. Upon carefulevaporation of the solvent, the desired solid salt is obtained.

[0049] The acids which can be used to prepare the pharmaceuticallyacceptable acid addition salts of the base compounds of this inventionare those which form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as chloride,bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acidphosphate, acetate, lactate, citrate or acid citrate, tartrate orbitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate and pamoate [ie.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0050] A compound of the invention which is also acidic in nature, e.g.,contains a COOH or tetrazole moiety, is capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchpharmaceutically acceptable base addition salts include the alkali metalor alkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts can be prepared by conventional techniques. Thechemical bases which can be used as reagents to prepare thepharmaceutically acceptable base addition salts of this invention arethose which form non-toxic base salts with the herein described acidiccompounds of the invention. These non-toxic base salts include saltsderived from such pharmacologically acceptable cations as sodium,potassium, calcium and magnesium, etc. These salts can easily beprepared by treating the corresponding acidic compounds with an aqueoussolution containing the desired pharmacologically acceptable cations,and then evaporating the resulting solution to dryness, preferably underreduced pressure. Alternatively, they may also be prepared by mixinglower alkanolic solutions of the acidic compounds and the desired alkalimetal alkoxide together, and then evaporating the resulting solution todryness in the same manner as before. In either case, stoichiometricquantities of reagents are preferably employed in order to ensurecompleteness of reaction and maximum product yields.

[0051] Isotopically-labeled compounds are also encompassed by thepresent invention. As used herein, an “isotopically-labeled compound”refers to a compound of the invention including pharmaceutical salts,prodrugs thereof, each as described herein, in which one or more atomsare replaced by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl respectively.

[0052] By isotopically-labeling a compound of the present invention, thecompounds may be useful in drug and/or substrate tissue distributionassays. Tritiated (³H) and carbon-14 (¹⁴C) labeled compounds areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium (²H) canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the invention, includingpharmaceutical salts, prodrugs thereof, can be prepared by any meansknown in the art.

[0053] Stereoisomers (e.g., cis and trans isomers) and all opticalisomers of a compound of the invention (e.g., R and S enantiomers), aswell as racemic, diastereomeric and other mixtures of such isomers arecontemplated by the present invention.

[0054] The compounds, salts, prodrugs, hydrates and solvates of thepresent invention can exist in several tautomeric forms, including theenol and imine form, and the keto and enamine form and geometric isomersand mixtures thereof. All such tautomeric forms are included within thescope of the present invention. Tautomers exist as mixtures of atautomeric set in solution. In solid form, usually one tautomerpredominates. Even though one tautomer may be described, the presentinvention includes all tautomers of the present compounds.

[0055] The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of the invention that can beseparated into rotationally restricted isomers.

[0056] A compound of the invention, as described above, can be used inthe manufacture of a medicament for the prophylactic or therapeutictreatment of a TGF-related disease state in a mammal (animal or human).

[0057] A compound of the invention is a potent inhibitor of transforminggrowth factor (“TGF”)-β signaling pathway and are therefore of use intherapy. Accordingly, the present invention provides a method ofpreventing or treating a TGF-related disease in a mammal (animal orhuman) comprising the step of administering a therapeutically effectiveamount of at least one compound of the invention to the animal or humansuffering from the TGF-related disease state.

[0058] As used herein, the term “therapeutically effective amount”refers to an amount of a compound of the invention required to inhibitthe TGF-β signaling pathway. As would be understood by one of skill inthe art, a “therapeutically effective amount” will vary from patient topatient and will be determined on a case by case basis. Factors toconsider include, but are not limited to, the patient being treated,weight, health, compound administered, etc.

[0059] There are numerous disease states that can be treated byinhibition of the TGF-β signaling pathway. Such disease states include,but are not limited to, all types of cancer (e.g., breast, lung, colon,prostate, ovarian, pancreatic, melanoma, all hematological malignancies,etc.) as well as all types of fibrotic diseases (e.g.,glomerulonephritis, diabetic nephropathy, hepatic fibrosis, pulmonaryfibrosis, arterial hyperplasia and restenosis, scleroderma, and dermalscarring).

[0060] The present invention also provides a pharmaceutical compositioncomprising at least one compound of the invention and at least onepharmaceutically acceptable carrier. The pharmaceutically acceptablecarrier may be any such carrier known in the art including thosedescribed in, for example, Remington's Pharmaceutical Sciences, MackPublishing Co., (A. R. Gennaro edit. 1985). A pharmaceutical compositionof the invention may be prepared by conventional means known in the artincluding, for example, mixing at least one compound of the inventionwith a pharmaceutically acceptable carrier.

[0061] A pharmaceutical composition of the invention may be used in theprevention or treatment of a TGF-related disease state, as describedabove, in a mammal (animal or human). Thus, a compound of the inventionmay be formulated as a pharmaceutical composition for oral, buccal,intranasal, parenteral (e.g., intravenous, intramuscular orsubcutaneous), topical or rectal administration or in a form suitablefor administration by inhalation or insufflation.

[0062] For oral administration, the pharmaceutical composition may takethe form of, for example, a tablet or capsule prepared by conventionalmeans with a pharmaceutically acceptable excipient such as a bindingagent (e.g., pregelatinized maize starch, polyvinylpyrrolidone orhydroxypropyl methylcellulose); filler (e.g., lactose, microcrystallinecellulose or calcium phosphate); lubricant (e.g., magnesium stearate,talc or silica); disintegrant (e.g., potato starch or sodium starchglycolate); or wetting agent (e.g., sodium lauryl sulphate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of a, for example, solution, syrupor suspension, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means with apharmaceutically acceptable additive such as a suspending agent (e.g.,sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g.,almond oil, oily esters or ethyl alcohol); and preservative (e.g.,methyl or propyl p-hydroxybenzoates or sorbic acid).

[0063] For buccal administration, the composition may take the form oftablets or lozenges formulated in conventional manner.

[0064] A compound of the present invention may also be formulated forsustained delivery according to methods well known to those of ordinaryskill in the art. Examples of such formulations can be found in U.S.Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397,which are herein incorporated by reference in their entirety.

[0065] A compound of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form, e.g., in ampules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain a formulating agent such as a suspending,stabilizing and/or dispersing agent. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

[0066] A compound of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

[0067] For intranasal administration or administration by inhalation, acompound of the invention may be conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the compound of theinvention. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

[0068] A proposed dose of a compound of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of a TGF-related disease state is about 0.1 mg to about 2000mg, preferably, about 0.1 mg to about 200 mg of the active ingredientper unit dose which could be administered, for example, 1 to 4 times perday.

[0069] Aerosol formulations for treatment of the conditions referred toabove in the average adult human are preferably arranged so that eachmetered dose or “puff” of aerosol contains about 20 μg to about 10,000μg, preferably, about 20 μg to about 1000 μg of a compound of theinvention. The overall daily dose with an aerosol will be within therange about 100 μg to about 100 mg, preferably, about 100 μg to about 10mg. Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

[0070] Aerosol combination formulations for treatment of the conditionsreferred to above in the average adult human are preferably arranged sothat each metered dose or “puff” of aerosol contains from about 0.01 mgto about 1000 mg, preferably, about 0.01 mg to about 100 mg of acompound of this invention, more preferably from about 1 mg to about 10mg of such compound. Administration may be several times daily, forexample 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses eachtime.

[0071] Aerosol formulations for treatment of the conditions referred toabove in the average adult human are preferably arranged so that eachmetered dose or “puff” of aerosol contains from about 0.01 mg to about20,000 mg, preferably, about 0.01 mg to about 2000 mg of a compound ofthe invention, more preferably from about 1 mg to about 200 mg.Administration may be several times daily, for example 2, 3, 4 or 8times, giving for example, 1, 2 or 3 doses each time.

[0072] For topical administration, a compound of the invention may beformulated as an ointment or cream.

[0073] This invention also encompasses pharmaceutical compositionscontaining and methods of treatment or prevention comprisingadministering prodrugs of at least one compound of the invention. Asused herein, the term “prodrug” refers to a pharmacologically inactivederivative of a parent drug molecule that requires biotransformation,either spontaneous or enzymatic, within the organism to release theactive drug. Prodrugs are variations or derivatives of the compounds ofthis invention which have groups cleavable under metabolic conditions.Prodrugs become the compounds of the invention which arepharmaceutically active in vivo, when they undergo solvolysis underphysiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry ofDrug Design and Drug Action, pp. 352-401, Academic Press, San Diego,Calif., 1992). Prodrugs commonly known in the art include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acids with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine, or basic groups reacted to form an acylated base derivative.Moreover, the prodrug derivatives of this invention may be combined withother features herein taught to enhance bioavailability. For example, acompound of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues which arecovalently joined through peptide bonds to free amino, hydroxy orcarboxylic acid groups of compounds of the invention. The amino acidresidues include the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also include, 4-hydroxyproline,hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin,beta-alanine, gamma-aminobutyric acid, citrulline homocysteine,homoserine, ornithine and methionine sulfone. Prodrugs also includecompounds wherein carbonates, carbamates, amides and alkyl esters whichare covalently bonded to the above substituents of a compound of theinvention through the carbonyl carbon prodrug sidechain.

[0074] According to the invention, in the treatment of a TGF-relateddisease state, a compound of the invention, as described herein, whetheralone or as part of a pharmaceutical composition may be combined withanother compound(s) of the invention and/or with another therapeuticagent(s). Examples of suitable therapeutic agent(s) include, but are notlimited to, standard non-steroidal anti-inflammatory agents (hereinafterNSAID's) (e.g, piroxicam, diclofenac), propionic acids (e.g., naproxen,flubiprofen, fenoprofen, ketoprofen and ibuprofen), fenamates (e.g.,mefenamic acid, indomethacin, sulindac, apazone), pyrazolones (e.g.,phenylbutazone), salicylates (e.g., aspirin), COX-2 inhibitors (e.g.,celecoxib, valdecoxib, rofecoxib and etoricoxib), analgesics andintraarticular therapies (e.g., corticosteroids) and hyaluronic acids(e.g., hyalgan and synvisc), anticancer agents (e.g., endostatin andangiostatin), cytotoxic drugs (e.g., adriamycin, daunomycin,cis-platinum, etoposide, taxol, taxotere), alkaloids (e.g.,vincristine), and antimetabolites (e.g., methotrexate), cardiovascularagents (e.g., calcium channel blockers), lipid lowering agents (e.g.,statins), fibrates, beta-blockers, Ace inhibitors, Angiotensin-2receptor antagonists and platelet aggregation inhibitors, CNS agents(e.g., as antidepressants (such as sertraline)), anti-Parkinsonian drugs(e.g., deprenyl, L-dopa, Requip, Mirapex), MAOB inhibitors (e.g.,selegine and rasagiline), comP inhibitors (e.g., Tasmar), A-2inhibitors, dopamine reuptake inhibitors, NMDA antagonists, Nicotineagonists, Dopamine agonists and inhibitors of neuronal nitric oxidesynthase), anti-Alzheimer's drugs (e.g., donepezil, tacrine, COX-2inhibitors, propentofylline or metryfonate), osteoporosis agents (e.g.,roloxifene, droloxifene, lasofoxifene or fosomax), and immunosuppressantagents (e.g., FK-506 and rapamycin).

[0075] The following Examples illustrate the preparation of thecompounds of the present invention. Melting points are uncorrected. NMRdata are reported in parts per million (d) and are referenced to thedeuterium lock signal from the sample solvent (deuteriochloroform unlessotherwise specified). Mass Spectral data were obtained using a MicromassZMD APCI Mass Spectrometer equipped with a Gilson gradient highperformance liquid chromatograph. The following solvents and gradientswere used for the analysis. Solvent A; 98% water/2% acetonirile/0.01%formic acid and solvent B; acetonitrile containing 0.005% formic acid.Typically, a gradient was run over a period of about 4 minutes startingat 95% solvent A and ending with 100% solvent B. The mass spectrum ofthe major eluting component was then obtained in positive or negativeion mode scanning a molecular weight range from 165 AMU to 1100 AMU.Specific rotations were measured at room temperature using the sodium Dline (589 nm). Commercial reagents were utilized without furtherpurification. THF refers to tetrahydrofuran. DMF refers toN,N-dimethylformamide. Chromatography refers to column chromatographyperformed using 32-63 mm silica gel and executed under nitrogen pressure(flash chromatography) conditions. Room or ambient temperature refers to20-25° C. All non-aqueous reactions were run under a nitrogen atmospherefor convenience and to maximize yields. Concentration at reducedpressure means that a rotary evaporator was used.

[0076] One of ordinary skill in the art will appreciate that in somecases protecting groups may be required during preparation. After thetarget molecule is made, the protecting group can be removed by methodswell known to those of ordinary skill in the art, such as described inGreene and Wuts, “Protective Groups in Organic Synthesis” (2^(nd) Ed,John Wiley & Sons 1991).

Biological Activity

[0077] The activity of the compounds of the invention for the variousTGF-related disease states described herein can be determined accordingto one or more of the following assays. According to the invention, acompound of the invention exhibits an in vitro IC₅₀ value of about0.0001 μM-10 μM. By way of illustration, the compound of example 35, asset forth below, exhibits an IC₅₀ of 1.19 μM.

[0078] The compounds of the present invention also possess differentialactivity (i.e. are selective for) for TβRII over TβRI and TβRIII.Selectivity is measured in standard assays as a IC₅₀ ratio of inhibitionin each assay.

TGF-β Type II Receptor (TβRII) Kinase Assay Protocol

[0079] Phosphorylation of myelin basic protein (MBP) by the TβRII kinasewas measured as follows: 80 microliters of MBP (Upstate Biotechnology#13-104) diluted in kinase reaction buffer (KRB) containing 50 mM MOPS,5 mM MgCl₂, pH 7.2 to yield a final concentration of 3 micromolar MBPwas added to each well of a Millipore 96-well multiscreen-DP 0.65 micronfiltration plate (#MADPNOB50). 20 microliters of inhibitor diluted inKRB was added to appropriate wells to yield the desired finalconcentration (10−0.03 micromolar). 10 microliters of a mixture of ATP(Sigma #A-5394) and ³³P-ATP (Perkin Elmer #NEG/602H) diluted in KRB wasadded to yield a final concentration of 0.25 micromolar ATP and 0.02microcuries of ³³P-ATP per well. 10 micro liters of a GST-TβRII fusionprotein (glutathione S-transferase at the N-terminal end of thecytoplasmic domain of TβRII-amino acids 193-567 with A to V change at438) diluted in KRB was added to each well to yield a finalconcentration of 27 nanomolar GST-TβRII. Plates were mixed and incubatedfor 90 minutes at room temperature. After the reaction incubation, 100microliters of cold 20% trichloroacetic acid (Aldrich #25,139-9) wasadded per well and plates were mixed and incubated for 60 minutes at 4°C. Liquid was then removed from the wells using a Millipore vacuummanifold. Plates were washed once with 200 microliters per well of cold10% trichloroacetic acid followed by two washes with 100 microliters perwell of cold 10% trichloroacetic acid. Plates were allowed to dryovernight at room temperature. 20 microliters of Wallac OptiPhaseSuperMix scintillation cocktail was added to each well. Plates weresealed and counted using a Wallac 1450 Microbeta liquid scintillationcounter. The potency of inhibitors was determined by their ability toreduce TβRII-mediated phosphorylation of the MBP substrate.

ALK-5 (TβRI) Kinase Assay Protocol

[0080] The kinase assays were performed with 65 nM GST-ALK5 and 84 nMGST-Smad3 in 50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, 1 mM dithiothreitol,and 3_M ATP. Reactions were incubated with 0.5_Ci of [33 P]_ATPfor 3 hat 30° C. Phosphorylated protein was captured on P-81 paper (Whatman,Maidstone, England), washed with 0.5% phosphoric acid, and counted byliquid scintillation. Alternatively, Smad3 or Smad1 protein was alsocoated onto FlashPlate Sterile Basic Microplates (PerkinElmer LifeSciences, Boston, Mass.). Kinase assays were then performed inFlash-Plates with same assay conditions using either the kinase domainof ALK5 with Smad3 as substrate or the kinase domain of ALK6 (BMPreceptor) with Smad1 as substrate. Plates were washed three times withphosphate buffer and counted by TopCount (Packard Bio-science, Meriden,Conn.). (Laping, N.J. et al. Molecular Pharmacology 62:58-64 (2002)).

EXAMPLES Example 1

[0081] Step A. Boronic Acid Coupling

[0082] 0.15 eq. palladium (II) acetate and 0.2 eq.1,1′-bis(diphenylphosphino)-ferrocene were combined in dimethylformamideunder nitrogen and heated to 50° C. for 20 minutes. R³ and n are each asdefined herein. The reaction was allowed to cool to room temperature and1.0 eq. of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. oftriethylamine were added. The reaction was heated to 90° for 12 hoursand allowed to cool to room temperature. The DMF was removed by rotaryevaporation. The crude reaction mixture was dissolved in chloroform andwashed twice with 1N aq. HCl and then twice with saturated aq. NaHCO₃solution. The organic layer was dried over sodium sulfate, filtered andconcentrated. Material was purified by silica gel chromatography using100% chloroform as eluent.

[0083] Step B. Hydrolysis to Acid

[0084] The pyrazine ester (1.0 eq) of Step A was suspended in ethanoland (aq) 3M sodium hydroxide (2.01 eq). The resulting solution wasrefluxed for 90 minutes. The reaction mixture was allowed to cool toroom temperature and 2.01 eq of aq. 3M hydrochloric acid (2.01 eq) wasadded. After stirring for 60 minutes, the reaction mixture wasconcentrated to dryness. The acid was used without further purificationin Step C below.

[0085] Step C. Amide Formation

[0086] 1.0 eq of a 0.2M solution of the acid of Step B inN,N-dimethylacetamide with 3.75% triethylamine was combined with 1.0 eqof a 0.2M solution of the amine R²NH₂ in N,N-dimethylacetamide with3.75% N-methylmorpholine and 1.5 eq of 0.3M2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroboratein N,N-dimethylacetamide. R², R³ and n are each as defined herein. Theresulting solution was shaken at 60° C. for 6 hours, and then at roomtemperature overnight. The reaction mixture was quenched with aq. 10%sodium hydroxide and extracted twice with ethyl acetate. The organiclayers dried over sodium sulfate, filtered, and concentrated. Crudereaction mixtures were purified by preparative HPLC.

Example 2

[0087] Step A. Boronic Acid Coupling

[0088] 0.15 eq. palladium (II) acetate and 0.2 eq.1,1′-bis(diphenylphosphino)-ferrocene were combined in dimethylformamideunder nitrogen and heated to 50° C. for 20 minutes. Het is as definedherein. The reaction was allowed to cool to room temperature and 1.0 eq.of the pyrazine, 1.5 eq. of the boronic acid and 1.15 eq. oftriethylamine were added. The reaction was heated to 90° for 12 hoursand allowed to cool to room temperature. The DMF was removed by rotaryevaporation. The crude reaction mixture was dissolved in chloroform andwashed twice with 1N aq. HCl and then twice with saturated aq. NaHCO₃solution. The organic layer was dried over sodium sulfate, filtered andconcentrated. Material was purified by silica gel chromatography using100% chloroform as eluent.

[0089] Step B. Hydrolysis to Acid

[0090] The pyrazine ester (1.0 eq) of Step A was suspended in ethanoland (aq) 3M sodium hydroxide (2.01 eq). Het is as defined herein. Theresulting solution was refluxed for 90 minutes. The reaction mixture wasallowed to cool to room temperature and 2.01 eq of aq. 3M hydrochloricacid (2.01 eq) was added. After stirring for 60 minutes, the reactionmixture was concentrated to dryness. The acid was used without furtherpurification in Step C below.

[0091] Step C. Amide Formation

[0092] 1.0 eq of a 0.2M solution of the acid of Step B inN,N-dimethylacetamide with 3.75% triethylamine was combined with 1.0 eqof a 0.2M solution of the amine R²NH₂ in N,N-dimethylacetamide with3.75% N-methylmorpholine and 1.5 eq of 0.3M2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroboratein N,N-dimethylacetamide. R² and Het are each as defined herein. Theresulting solution was shaken at 60° C. for 6 hours, and then at roomtemperature overnight. The reaction mixture was quenched with aq. 10%sodium hydroxide and extracted twice with ethyl acetate. The organiclayers dried over sodium sulfate, filtered, and concentrated. Crudereaction mixtures were purified by preparative HPLC.

Examples 3-176

[0093] Examples of a compound of formula (I), as described above, areset forth in the Table 1 below. Each of the compounds may be preparedfollowing the procedure set forth in Example 1. TABLE 1 (I)

R³ Example R¹ R² where n = 1  3 H —CH₂Ph H LC-MS (M+) = 305; HPLC (Tr(min)) = 6.16  4 H n-butyl 4-methyl LC-MS (M+) = 285; HPLC (Tr (min)) =7.77  5 H n-butyl 4-chloro LC-MS (M+) = 305; HPLC (Tr (min)) = 7.94  6R¹ and R² taken together with the nitrogen to which 4-methyl LC-MS (M+)= 283; they are attached: HPLC (Tr (min)) = 6.65

 7 R¹ and R² taken together with the nitrogen to which 4-chloro LC-MS(M+) = 303; they are attached: HPLC (Tr (min)) = 6.91

 8 H cyclohexyl H LC-MS (M+) = 297; HPLC (Tr (min)) = 6.79  9 H n-butylH LC-MS (M+) = 271; HPLC (Tr (min)) = 6.19  10 H cyclopentyl H LC-MS(M+) = 283; HPLC (Tr (min)) = 5.65  11 H cycloheptyl H LC-MS (M+) = 311;HPLC (Tr (min)) = 7.2  12 H phenyl H LC-MS (M+) = 291; HPLC (Tr (min)) =6.57  13 R¹ and R² taken together with the nitrogen H LC-MS (M+) = 269;to which they are attached: HPLC (Tr (min)) = 5

 14 LC-MS (M+) = 331; HPLC (Tr (min)) = 6.77 H

H  15 H —(CH₂)₃—N(CH₃)₂ H LC-MS (M+) = 300; HPLC (Tr (min)) = 3.47  16 H—(CH₂)C(CH₃)₂—CH₂N(CH₃)₂ H LC-MS (M+) = 328; HPLC (Tr (min)) = 3.91  17H benzyl 4-chloro LC-MS (M+) = 339; HPLC (Tr (min)) = 6.78  18 Hcyclopentyl 4-chloro LC-MS (M+) = 317; HPLC (Tr (min)) = 6.98  19 Hcycloheptyl 4-chloro LC-MS (M+) = 345; HPLC (Tr (min)) = 7.83  20 Hcyclohexyl 4-chloro LC-MS (M+) = 331; HPLC (Tr (min)) = 7.42  21 Hn-butyl 3-chloro LC-MS (M+) = 305; HPLC (Tr (min)) = 6.8  22 Hcyclopentyl 3-chloro LC-MS (M+) = 317; HPLC (Tr (min)) = 6.94  23 Hcycloheptyl 3-chloro LC-MS (M+) = 345; HPLC (Tr (min)) = 7.8  24 Hcyclohexyl 3-chloro LC-MS (M+) = 331; HPLC (Tr (min)) = 7.39  25 R¹ andR² taken together with the nitrogen to which 3-chloro LC-MS (M+) = 303;they are attached: HPLC (Tr (min)) = 5.74

 26 H benzyl 2-chloro LC-MS (M+) = 339; HPLC (Tr (min)) = 6.55  27 Hn-butyl 2-chloro LC-MS (M+) = 305; HPLC (Tr (min)) = 6.55  28 Hcyclopentyl 2-chloro LC-MS (M+) = 317; HPLC (Tr (min)) = 6.67  29 Hcycloheptyl 2-chloro LC-MS (M+) = 345; HPLC (Tr (min)) = 7.55  30 Hcyclohexyl 2-chloro LC-MS (M+) = 331; HPLC (Tr (min)) = 7.14  31 R¹ andR² taken together with the nitrogen to which 2-chloro LC-MS (M+) = 303;they are attached: HPLC (Tr (min)) = 5.26

 32 H benzyl 4-methyl LC-MS (M+) = 319; HPLC (Tr (min)) = 6.62  33 Hcyclopentyl 4-methyl LC-MS (M+) = 297; HPLC (Tr (min)) = 6.78  34 Hcycloheptyl 4-methyl LC-MS (M+) = 325; HPLC (Tr (min)) = 7.66  35 Hcyclohexyl 4-methyl LC-MS (M+) = 311; HPLC (Tr (min)) = 7.24  36 Hbenzyl 4-methoxy LC-MS (M+) = 335; HPLC (Tr (min)) = 6.17  37 H n-butyl4-methoxy LC-MS (M+) = 301; HPLC (Tr (min)) = 6.13  38 H cyclopentyl4-methoxy LC-MS (M+) = 313; HPLC (Tr (min)) = 6.25  39 H cycloheptyl4-methoxy LC-MS (M+) = 341; HPLC (Tr (min)) = 7.1  40 H cyclohexyl4-methoxy LC-MS (M+) = 327; HPLC (Tr (min)) = 6.7  41 H phenyl 4-methoxyLC-MS (M+) = 321; HPLC (Tr (min)) = 6.54  42 R¹ and R² taken togetherwith the nitrogen to which 4-methoxy LC-MS (M+) = 299; they areattached: HPLC (Tr (min)) = 4.99

 43 H —CH(CH₃)Ph 4-methoxy LC-MS (M+) = 349; HPLC (Tr (min)) = 6.48  44LC-MS (M+) = 361; HPLC (Tr (min)) = 6.70 H

4-methoxy  45 LC-MS (M+) = 356 H

4-methoxy  46 H —CH₂-2-pyridyl 4-methoxy LC-MS (M+) = 336; HPLC (Tr(min)) = 4.97  47 H —(CH₂)₂—NHC(═O)CH₃ 4-methoxy LC-MS (M+) = 330; HPLC(Tr (min)) = 4.01  48 H —(CH₂)₄Ph 4-methoxy LC-MS (M+) = 377; HPLC (Tr(min)) = 7.06  49 LC-MS (M+) = 404; HPLC (Tr (min)) = 4.49 H

4-methoxy  50 H —(CH₂)₂-2-pyridyl 4-methoxy LC-MS (M+) = 350 HPLC (Tr(min)) = 5.01  51 LC-MS (M+) = 447 HPLC (Tr (min)) = 4.51 H

4-methoxy  52 H —CH₂C(CH₃)₂CH₂N(CH₃)₂ 4-methoxy LC-MS (M+) = 358; HPLC(Tr (min)) = 3.95  53 LC-MS (M+) = 357 H

4-methoxy  54 LC-MS (M+) = 379 HPLC (Tr (min)) = 5.48 H

4-methoxy  55 LC-MS (M+) = 441 HPLC (Tr (min)) = 6.33 H

4-methoxy  56 LC-MS (M+) = 377; HPLC (Tr (min)) = 5.61 H

4-methoxy  57 LC-MS (M+) = 365 HPLC (Tr (min)) = 5.31 H

4-methoxy  58 H —CH(CH₂OH)₂ 4-methoxy LC-MS (M−) = 317; HPLC (Tr (min))= 3.65  59 H —(CH₂)₂OH 4-methoxy LC-MS (M+) = 289 HPLC (Tr (min)) = 3.97 60 LC-MS (M+) = 357; HPLC (Tr (min)) = 5.53 H

4-methoxy  61 H —CH₂C(CH₃)₂CH₂OH 4-methoxy LC-MS (M+) = 331; HPLC (Tr(min)) = 5.09  62 LC-MS (M+) = 372; HPLC (Tr (min)) = 3.62 H

4-methoxy  63 LC-MS (M+) = 326 H

H  64 H —CH₂-2-pyridyl H LC-MS (M+) = 306; HPLC (Tr (min)) = 4.95  65 H—(CH₂)₂—NHC(═O)CH₃ H LC-MS (M+) = 300; HPLC (Tr (min)) = 3.94  66 H—(CH₂)₂—OCH₃ H LC-MS (M+) = 273 HPLC (Tr (min)) = 4.75  67 H —(CH₂)₄Ph HLC-MS (M+) = 347; HPLC (Tr (min)) = 7.15  68 LC-MS (M+) = 374 HPLC (Tr(min)) = 4.43 H

H  69 H —(CH₂)₂-2-pyridyl H LC-MS (M+) = 320 HPLC (Tr (min)) = 4.99  70LC-MS (M+) = 417 HPLC (Tr (min)) = 4.45 H

H  71 LC-MS (M+) = 327 HPLC (Tr (min)) = 5.61 H

H  72 H —CH(CH₃)(CH₂)₃C(CH₃)₂OH H LC-MS (M+) = 343/325; HPLC (Tr (min))= 5.55  73 LC-MS (M+) = 349 HPLC (Tr (min)) = 5.49 H

H  74 LC-MS (M+) = 411; HPLC (Tr (min)) = 6.38 H

H  75 LC-MS (M+) = 347; HPLC (Tr (min)) = 5.60 H

H  76 LC-MS (M+) = 335 HPLC (Tr (min)) = 5.31 H

H  77 H —CH(CH₂OH)₂ H LC-MS (M+) = 289; HPLC (Tr (min)) = 3.55  78 H—(CH₂)₂OH H LC-MS (M+) = 259 HPLC (Tr (min)) = 3.88  79 LC-MS (M+) =327; HPLC (Tr (min)) = 5.53 H

H  80 H —CH₂C(CH₃)₂CH₂OH H LC-MS (M+) = 301; HPLC (Tr (min)) = 5.07  81LC-MS (M+) = 327 HPLC (Tr (min)) = 4.6 H

4-methyl  82 LC-MS (M+) = 427 H

4-SO₂CH₃  83 LC-MS (M+) = 489 H

4-SO₂CH₃  84 LC-MS (M+) = 361 H

4-methyl  85 LC-MS (M+) = 349 H

4-methyl  86 LC-MS (M+) = 413 H

4-SO₂CH₃  87 H —CH(CH₂OH)₂ 4-methyl LC-MS (M+) = 303  88 H —CH(CH₂OH)₂4-SO₂CH₃ LC-MS (M+) = 367  89 H —(CH₂)₂OH 4-methyl LC-MS (M+) = 273 HPLC(Tr (min)) = 4.36  90 H —CH₂C(CH₃)₂CH₂OH 4-methyl LC-MS (M+) = 315 HPLC(Tr (min)) = 5.52  91 H —CH₂C(CH₃)₂CH₂OH 4-SO₂CH₃ LC-MS (M+) = 379 HPLC(Tr (min)) = 4.30  92 LC-MS (M+) = 383 H

4-chloro  93 LC-MS (M+) = 383 H

3-chloro  94 LC-MS (M+) = 383 H

2-chloro  95 LC-MS (M+) = 381 H

4-chloro  96 LC-MS (M+) = 381 H

3-chloro  97 LC-MS (M+) = 381 H

2-chloro  98 LC-MS (M+) = 369 H

4-chloro  99 LC-MS (M+) = 369 H

3-chloro 100 LC-MS (M+) = 369 H

2-chloro 101 H —CH(CH₂OH)₂ 4-chloro LC-MS (M+) = 323 102 H —CH(CH₂OH)₂3-chloro LC-MS (M+) = 323 103 H —CH(CH₂OH)₂ 2-chloro LC-MS (M+) = 323104 H —(CH₂)₂OH 4-chloro LC-MS (M+) = 293 105 H —(CH₂)₂OH 3-chloro LC-MS(M+) = 293 HPLC (Tr (min)) = 4.50 106 H —(CH₂)₂OH 2-chloro LC-MS (M+) =293 HPLC (Tr (min)) = 4.23 107 H —CH₂C(CH₃)₂CH₂OH 3-chloro LC-MS (M+) =335 HPLC (Tr (min)) = 5.70 108 H —CH₂C(CH₃)₂CH₂OH 2-chloro LC-MS (M+) =335 HPLC (Tr (min)) = 5.39 109 H —(CH₂)₂-2-pyridyl 4-methyl LC-MS (M+) =334 110 H —(CH₂)₂-2-pyridyl 4-SO₂CH₃ LC-MS (M+) = 398 111 H—(CH₂)₂-2-pyridyl 4-chloro LC-MS (M+) = 354 112 H —(CH₂)₂-2-pyridyl3-chloro LC-MS (M+) = 354 113 H —(CH₂)₂-2-pyridyl 2-chloro LC-MS (M+) =354 114 H —(CH₂)₂—NHC(═O)CH₃ 4-chloro LC-MS (M+) = 334 115 H—(CH₂)₂—NHC(═O)CH₃ 3-chloro LC-MS (M+) = 334 116 H cyclopentyl 4-SO₂CH₃LC-MS (M+) = 361 117 LC-MS (M+) = 340 H

4-methyl 118 H —CH₂C(CH₃)₂CH₂OH H LC-MS (M+) = 301 HPLC (Tr (min)) =5.06 119 H —CH₂C(CH₃)₂CH₂OH 4-methoxy LC-MS (M+) = 331 HPLC (Tr (min)) =5.08 120 H —CH₂CH(OH)CH₂OH H LC-MS (M+) = 289 HPLC (Tr (min)) = 3.62 121H —CH₂CH(OH)CH₂OH 3-chloro LC-MS (M+) = 323 HPLC (Tr (min)) = 4.19 122 H—CH₂CH(OH)CH₂OH 2-chloro LC-MS (M+) = 323 HPLC (Tr (min)) = 3.83 123 H—CH₂CH(OH)CH₂OH 4-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) = 3.72 124 H—CH₂CH(OH)CH₂OH 4-methyl LC-MS (M+) = 303 HPLC (Tr (min)) = 3.94 125 H—CH₂CH(OH)CH₂OH 3-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) = 3.79 126 H—CH₂CH(OH)CH₂OH 2-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) = 3.75 127 H—CH₂CH(OH)CH₂OH 4-CN LC-MS (M+) = 314 HPLC (Tr (min)) = 3.80 128 H—(CH₂)₃OH 3-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.26 129 H—(CH₂)₃OH 2-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.25 130 H—(CH₂)₃OH 4-CN LC-MS (M+) = 298 HPLC (Tr (min)) = 4.06 131 H —(CH₂)₂OH4-C(═O)CH₃ LC-MS (M+) = 301 HPLC (Tr (min)) = 3.70 132 H —(CH₂)₂OH3-methoxy LC-MS (M+) = 289 HPLC (Tr (min)) = 4.05 133 H —(CH₂)₂OH2-methoxy LC-MS (M+) = 289 HPLC (Tr (min)) = 4.02 134 H —(CH₂)₂OH 4-CNLC-MS (M+) = 284 HPLC (Tr (min)) = 3.80 135 H —CH₂C(CH₃)₂CH₂OH4-C(═O)CH₃ LC-MS (M+) = 343 HPLC (Tr (min)) = 4.75 136 H—CH₂C(CH₃)₂CH₂OH 3-methoxy LC-MS (M+) = 331 HPLC (Tr (min)) = 5.16 137 H—CH₂C(CH₃)₂CH₂OH 2-methoxy LC-MS (M+) = 331 HPLC (Tr (min)) = 5.17 138 H—CH₂C(CH₃)₂CH₂OH 4-CN LC-MS (M+) = 326 HPLC (Tr (min)) = 4.90 139 H—CH₂CH(OH)CH₂OH 4-C(═O)CH₃ LC-MS (M+) = 331 HPLC (Tr (min)) = 3.50 140 H—CH₂CH(OH)CH₂OH 2,3-dichloro LC-MS (M+) = 358 HPLC (Tr (min)) = 4.71 141H —(CH₂)₃OH 2-chloro LC-MS (M+) = 307 HPLC (Tr (min)) = 4.45 142 H—(CH₂)₃OH 4-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.18 143 H—(CH₂)₃OH 4-C(═O)CH₃ LC-MS (M+) = 315 HPLC (Tr (min)) = 3.95 144 H—(CH₂)₃CH 4-bromo LC-MS (M+) = 351 HPLC (Tr (min)) = 4.90 145 H—(CH₂)₂CH 2,3-dichloro LC-MS (M+) = 328 HPLC (Tr (min)) = 5.06 146 H—(CH₂)₂CH 4-bromo LC-MS (M+) = 337 HPLC (Tr (min)) = 4.68 147 H—CH₂C(CH₃)₂CH₂OH 2,3-dichloro LC-MS (M+) = 370 HPLC (Tr (min)) = 6.24148 H —CH₂C(CH₃)₂CH₂OH 4-bromo LC-MS (M+) = 379 HPLC (Tr (min)) = 5.84149 H —(CH₂)₂OCH₃ 4-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.78 150LC-MS (M+) = 353 HPLC (Tr (min)) = 3.75 H

4-methoxy 151 H —CH₂CH(OH)CH₂OH H LC-MS (M+) = 289 HPLC (Tr (min)) =3.62 152 H —CH₂CH(OH)CH₂OH 3-chloro LC-MS (M+) = 323 HPLC (Tr (min)) =4.19 153 H —CH₂CH(OH)CH₂OH 2-chloro LC-MS (M+) = 323 HPLC (Tr (min)) =3.83 154 H —CH₂CH(OH)CH₂OH 4-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) =3.72 155 H —CH₂CH(OH)CH₂OH 3-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) =3.79 156 H —CH₂CH(OH)CH₂OH 2-methoxy LC-MS (M+) = 319 HPLC (Tr (min)) =3.75 157 H —CH₂CH(OH)CH₂OH 4-CN LC-MS (M+) = 214 HPLC (Tr (min)) = 3.80158 H —(CH₂)₃OH 3-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.26 159 H—(CH₂)₃OH 2-methoxy LC-MS (M+) = 303 HPLC (Tr (min)) = 4.25 160 H—(CH₂)₃OH 4-CN LC-MS (M+) = 298 HPLC (Tr (min)) = 4.06 161 H —(CH₂)₂OH HLC-MS (M+) = 259 HPLC (Tr (min)) = 3.88 162 H —(CH₂)₂OH 3-chloro LC-MS(M+) = 293 HPLC (Tr (min)) = 4.50 163 H —(CH₂)₂OH 2-chloro LC-MS (M+) =293 HPLC (Tr (min)) = 4.23 164 H —(CH₂)₂OH 4-methyl LC-MS (M+) = 273HPLC (Tr (min)) = 4.36 165 H —(CH₂)₂OH 4-methoxy LC-MS (M+) = 289 HPLC(Tr (min)) = 3.97 166 H —(CH₂)₂OH 4-C(═O)CH₃ LC-MS (M+) = 301 HPLC (Tr(min)) = 3.70 167 H —(CH₂)₂OH 3-methoxy LC-MS (M+) = 289 HPLC (Tr (min))= 4.05 168 H —(CH₂)₂OH 2-methoxy LC-MS (M+) = 289 HPLC (Tr (min)) = 4.02169 H —(CH₂)₂OH 4-CN LC-MS (M+) = 284 HPLC (Tr (min)) = 3.80 170 H—CH₂C(CH₃)₂CH₂OH 3-chloro LC-MS (M+) = 335 HPLC (Tr (min)) = 5.70 171 H—CH₂C(CH₃)₂CH₂OH 2-chloro LC-MS (M+) = 335 HPLC (Tr (min)) = 5.39 172 H—CH₂C(CH₃)₂CH₂OH 4-SO₂CH₃ LC-MS (M+) = 379 HPLC (Tr (min)) = 4.30 173 H—CH₂C(CH₃)₂CH₂OH 4-C(═O)CH₃ LC-MS (M+) = 343 HPLC (Tr (min)) = 4.75 174H —CH₂C(CH₃)₂CH₂OH 3-methoxy LC-MS (M+) = 331 HPLC (Tr (min)) = 5.16 175H —CH₂C(CH₃)₂CH₂OH 2-methoxy LC-MS (M+) = 331 HPLC (Tr (min)) = 5.17 176H —CH₂C(CH₃)₂CH₂OH 4-CN LC-MS (M+) = 326 HPLC (Tr (min)) = 4.90

Examples 177-214

[0094] Examples of a compound of formula (II), as described above, areset forth in in Table 2 below. Each of the compounds may be preparedaccording to the procedure set forth in Example 2. TABLE 2 (II)

Compound R¹ R² Het 177 LC-MS (M+) = 339 H

2-furanyl 178 LC-MS (M+) = 355 H

3-thienyl 179 LC-MS (M+) = 417 H

3-thienyl 180 LC-MS (M+) = 353 H

3-thienyl 181 LC-MS (M+) = 325 H

2-furanyl 182 LC-MS (M+) = 341 H

3-thienyl 183 H —CH(CH₂OH)₂ 3-thienyl LC-MS (M+) = 295 184 H —(CH₂)₂OH3-thienyl LC-MS (M+) = 265 HPLC (Tr (min)) = 3.69 185 H —CH₂C(CH₃)₂CH₂OH3-thienyl LC-MS (M+) = 307 HPLC (Tr (min)) = 4.88 186 LC-MS (M+) = 364 H

2-furanyl 187 LC-MS (M+) = 380 H

3-thienyl 188 H —(CH₂)₃-4-morpholinyl 2-furanyl LC-MS (M+) = 332 189 H—(CH₂)₃—N(CH₃)₂ 2-furanyl LC-MS (M+) = 290 190 H —(CH₂)₂-2-pyridyl3-thienyl LC-MS (M+) = 326 191 R¹ and R² taken together with the3-thienyl LC-MS (M+) = 301 nitrogen to which they are attached:

192 H —CH₂-2-pyridyl 3-thienyl LC-MS (M+) = 312 193 H —(CH₂)₂—NC(═O)CH₃3-thienyl LC-MS (M+) = 306 194 H cyclopentyl 3-thienyl LC-MS (M+) = 289195 H —CH(CH₃)Ph 3-thienyl LC-MS (M+) = 325 196 LC-MS (M+) = 337 H

3-thienyl 197 LC-MS (M+) = 332 H

3-thienyl 198 H —CH₂CH(OH)CH₂OH 2-thienyl-5- LC-MS (M+) = 337 acetylHPLC (Tr (min)) = 3.7 199 H —CH₂CH(OH)CH₂OH 2-benzo- LC-MS (M+) = 329furanyl HPLC (Tr (min)) = 4.20 200 H —(CH₂)₃OH 2-thienyl-5- LC-MS (M+) =321 acetyl HPLC (Tr (min)) = 3.80 201 H —(CH₂)₃OH 2-benzo- LC-MS (M+) =313 furanyl HPLC (Tr (min)) = 4.80 202 H —(CH₂)₂OH 2-benzo- LC-MS (M+) =299 furanyl HPLC (Tr (min)) = 4.6 203 H —CH₂C(CH₃)₂CH₂OH 2-thienyl-5-LC-MS (M+) = 349 acetyl HPLC (Tr (min)) = 4.7 204 H —(CH₂)₃OH 3-thienylLC-MS (M+) = 279 HPLC (Tr (min)) = 3.93 205 H —(CH₂)₂OH 2-thienyl-5-LC-MS (M+) = 307 acetyl HPLC (Tr (min)) = 3.70 206 H —CH₂C(CH₃)₂CH₂OH2-pyridyl LC-MS (M+) = 302 HPLC (Tr (min)) = 3.80 207 H —CH₂CH(OH)CH₂OH2-thienyl-5- LC-MS (M+) = 337 acetyl HPLC (Tr (min)) = 3.70 208 H—CH₂CH(OH)CH₂OH 2-benzo- LC-MS (M+) = 329 furanyl HPLC (Tr (min)) = 4.20209 H —(CH₂)₃OH 2-thienyl-5- LC-MS (M+) = 321 acetyl HPLC (Tr (min)) =3.80 210 H —(CH₂)₃OH 2-benzo- LC-MS (M+) = 313 furanyl HPLC (Tr (min)) =4.80 211 H —(CH₂)₂OH 2-benzo- LC-MS (M+) = 299 furanyl HPLC (Tr (min)) =4.60 212 H —CH₂C(CH₃)₂CH₂OH 3-thienyl LC-MS (M+) = 307 HPLC (Tr (min)) =4.88 213 H —CH₂C(CH₃)₂CH₂OH 2-furanyl LC-MS (M+) = 291 HPLC (Tr (min)) =4.75 214 H —CH₂C(CH₃)₂CH₂OH 2-thienyl-5- LC-MS (M+) = 349 acetyl HPLC(Tr (min)) = 4.70

Example 215-217

[0095] Examples of a compound of formula (III), as described above, areset forth in Table 3. Each of the compounds may be prepared by followingthe procedure set forth in Example 1. TABLE 3 (III)

Compound R¹ R² Ar 215 H —(CH₂)₃OH 1-naphthyl LC-MS (M+) = 323 HPLC(Tr(min)) = 4.87 216 H —CH₂C(CH₃)₂CH₂OH 1-naphthyl LC-MS (M+) = 351 HPLC(Tr(min)) = 5.79 217 H —CH₂C(CH₃)₂CH₂OH 1-naphthyl LC-MS (M+) = 351 HPLC(Tr(min)) = 5.79

[0096] All publications, including but not limited to, issued patents,patent applications, and journal articles, cited in this application areeach herein incorporated by reference in their entirety.

[0097] Although the invention has been described above with reference tothe disclosed embodiments, those skilled in the art will readilyappreciate that the specific experiments detailed are only illustrativeof the invention. It should be understood that various modifications canbe made without departing from the spirit of the invention. Accordingly,the invention is limited only by the following claims.

The claimed invention is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt, prodrug, hydrate or solvatethereof where: R¹ is H; R² is a substituted or unsubstituted(C₁-C₈)alkyl, (C₃-C_(y))cycloalkyl, (C₃-C₉)aryl, (C₃-C₉)heteroaryl,amide, amino, (C₁-C₈)alcohol, (C₃-C₉)heterocycloalkyl,(C₁-C₈)alkyl(C₃-C₉)aryl, (C₁-C₈)alkylamine, (C₁-C₈)alkylamide; or R₁ andR² taken together with the nitrogen to which they are attached form asubstituted or unsubstituted heterocycloalkyl or heteroaryl; R³ isindependently selected from the group consisting of H, (C₁-C₈)alkyl,halo, (C₁-C₈)alkoxy, sulfonyl, cyano, and keto; n is an integer from0-5; with the proviso that the compound is not3-amino-6-phenyl-pyrazine-2-carboxylic acid butylamide or³-amino-6-phenyl-pyrazine-2-carboxylic acid (2-hydroxy-ethyl)-amide. 2.A compound of claim 1, wherein R³ is H, bromo, chloro, cyano, methoxy,(C₁-C₈)alkyl-SO₂—, or (C₁-C₈)alkylC(═O)—.
 3. A compound of claim 1,wherein n is 0-4.
 4. A compound of claim 3, wherein n is 0-1.
 5. Acompound of formula (II):

or a pharmaceutically acceptable salt, prodrug, hydrate or solvatethereof where: R¹ is H; R² is a substituted or unsubstituted(C₁-C₈)alcohol, (C₃-C₉)cycloalkyl, (C₃-C₉)heterocycloalkyl,(C₃-C₉)heteroaryl, (C₁-C₈)alkylamine, (C₁-C₈)alkyl(C₃-C₉)aryl, or(C₁-C₈)alkylamide; or R¹ and R² taken together with the nitrogen towhich they are attached form a substituted or unsubstitutedheterocycloalkyl or heteroaryl group; Het is a substituted orunsubstituted heterocyclyl or heteroaryl group containing at least oneheteroatom selected from N, O and S.
 6. A compound of claim 5, whereinHet is a substituted or unsubstituted (C₅-C₁₀)heterocyclyl or heteroarylgroup containing at least one heteroatom selected from N, O and S.
 7. Acompound of claim 6, wherein Het is a substituted or unsubstitutedfuranyl, thienyl, pyridyl, or benzofuranyl group.
 8. A compound offormula (III):

or a pharmaceutically acceptable salt, prodrug, hydrate or solvatethereof where: R¹ is H; R² is a substituted or unsubstituted(C₁-C₈)alcohol; Ar is a substituted or unsubstituted (C₃-C₉)aryl group;with the proviso that the compound is not3-amino-6-phenyl-pyrazine-2-carboxylic acid butylamide or3-amino-6-phenyl-pyrazine-2-carboxylic acid (2-hydroxy-ethyl)-amide. 9.A compound of claim 8, wherein R² is a substituted or unsubstituted(C₁-C₅)alcohol.
 10. A compound of claim 9, wherein R² is a substitutedor unsubstituted (C₃-C₅)alcohol.
 11. A compound of claim 8, wherein Aris a substituted or unsubstituted naphthyl group.
 12. A pharmaceuticalcomposition comprising a compound of any one of claims 1-11 and apharmaceutically acceptable carrier.
 13. A method of preventing ortreating a TGF-related disease state in a mammal (animal or human)comprising the step of administering a therapeutically effective amountof a compound of any one of claims 1-11 to the animal or human sufferingfrom the TGF-related disease state.
 14. A method of claim 13, whereinsaid TGF-related disease state is selected from the group consisting ofcancer, glomerulonephritis, diabetic nephropathy, hepatic fibrosis,pulmonary fibrosis, intimal hyperplasia and restenosis, scleroderma, anddermal scarring.